Recommended Dose. 50 mg once daily. Treatment-naïve or treatment-experienced INSTInaïve. when coadministered with certain UGT1A or

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TIVICAY safely and effectively. See full prescribing information for TIVICAY. TIVICAY (dolutegravir) tablets, for oral use Initial U.S. Approval: RECENT MAJOR CHANGES Indications and Usage (1) 12/2014 Dosage and Administration (2.1, 2.2) 08/ INDICATIONS AND USAGE TIVICAY is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1) Limitations of Use: Use of TIVICAY in integrase strand transfer inhibitor (INSTI)- experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. (12.4) DOSAGE AND ADMINISTRATION May be taken without regard to meals. (2) Adult Population Recommended Dose Treatment-naïve or treatment-experienced INSTInaïve (2.1) once daily Treatment-naïve or treatment-experienced INSTInaïve when coadministered with certain UGT1A or twice daily CYP3A inducers (2.1, 7.3) INSTI-experienced with certain INSTI-associated twice daily resistance substitutions or clinically suspected INSTI resistance a (12.4) a Alternative combinations that do not include metabolic inducers should be considered where possible. Pediatric Patients: (Treatment-naïve or treatment-experienced INSTI-naïve, aged 12 years and older, and weighing at least 40 kg). (2.2) The recommended dose is TIVICAY once daily. If certain UGT1A or CYP3A inducers are coadministered, then the recommended dose of TIVICAY is twice daily. (2.2, 7.3) DOSAGE FORMS AND STRENGTHS Tablets: (3) CONTRAINDICATIONS Previous hypersensitivity reaction to dolutegravir. (4) Coadministration with dofetilide. (4) WARNINGS AND PRECAUTIONS Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. (5.1) Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY is recommended in patients with underlying hepatic disease such as hepatitis B or C. (5.2) Redistribution/accumulation of body fat and immune reconstitution syndrome have been reported in patients treated with combination antiretroviral therapy. (5.3, 5.4) ADVERSE REACTIONS The most common adverse reactions of moderate to severe intensity and incidence at least 2% (in those receiving TIVICAY in any one adult trial) are insomnia, fatigue, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at or FDA at FDA-1088 or DRUG INTERACTIONS Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. (7.2, 7.3) TIVICAY should be taken 2 hours before or 6 hours after taking cationcontaining antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food. (7.3) USE IN SPECIFIC POPULATIONS Pregnancy: TIVICAY should be used during pregnancy only if the potential benefit justifies the potential risk. (8.1) Nursing mothers: Breastfeeding is not recommended due to the potential for HIV transmission. (8.3) Pediatric patients: Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 08/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Pediatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection 5.3 Fat Redistribution 5.4 Immune Reconstitution Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Adult Subjects 6.2 Clinical Trials Experience in Pediatric Subjects 7 DRUG INTERACTIONS 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir 7.3 Established and Other Potentially Significant Drug Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adult Subjects 14.2 Pediatric Subjects 1

2 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2

3 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE TIVICAY is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use: Use of TIVICAY in integrase strand transfer inhibitor (INSTI)-experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R [see Microbiology (12.4)]. 2 DOSAGE AND ADMINISTRATION TIVICAY tablets may be taken with or without food. 2.1 Adults Table 1. Dosing Recommendations for TIVICAY in Adult Patients Recommended Population Dose Treatment-naïve or treatment-experienced INSTI-naïve once daily Treatment-naïve or treatment-experienced INSTI-naïve when twice daily coadministered with certain UGT1A or CYP3A inducers [see Drug Interactions (7.3) for relevant inducers] INSTI-experienced with certain INSTI-associated resistance twice daily substitutions or clinically suspected INSTI resistance a [see Microbiology (12.4)] a Alternative combinations that do not include metabolic inducers should be considered where possible [see Drug Interactions (7)]. The safety and efficacy of doses above twice daily have not been evaluated. 2.2 Pediatric Patients Treatment-naïve or Treatment-experienced INSTI-naïve The recommended dose of TIVICAY in pediatric patients aged 12 years and older and weighing at least 40 kg is administered orally once daily. If certain UGT1A or CYP3A inducers are coadministered, then the recommended dose of TIVICAY is twice daily [see Drug Interactions (7.3) for relevant inducers]. 3

4 Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years or weighing less than 40 kg, or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). 3 DOSAGE FORMS AND STRENGTHS TIVICAY 50-mg tablets are yellow, round, film-coated, biconvex tablets debossed with SV 572 on one side and 50 on the other side. Each tablet contains of dolutegravir (as dolutegravir sodium) [see Description (11)]. 4 CONTRAINDICATIONS TIVICAY is contraindicated in patients: with previous hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.1)]. receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir. 5.2 Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY [see Adverse Reactions (6.1)]. In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY are recommended in patients with underlying hepatic disease such as hepatitis B or C. 4

5 5.3 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 6 ADVERSE REACTIONS The following adverse drug reactions (adverse events assessed as causally related by the investigator or ADRs) are discussed in other sections of the labeling: Hypersensitivity reactions [see Warnings and Precautions (5.1)]. Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see Warnings and Precautions (5.2)]. Fat Redistribution [see Warnings and Precautions (5.3)]. Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience in Adult Subjects Treatment-emergent Adverse Drug Reactions (ADRs) Treatment-naïve Subjects: The safety assessment of TIVICAY in HIV-1-infected treatmentnaïve subjects is based on the analyses of 96-week data from 2 international, multicenter, doubleblind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial. 5

6 In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM ] or emtricitabine/tenofovir [TRUVADA ]). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA ) once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY once daily + EPZICOM and 12% in subjects receiving ATRIPLA once daily. Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. 6

7 Table 2. Treatment-emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-naïve Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysis) TIVICAY Once Daily + 2 NRTIs (n = 403) SPRING-2 Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY + EPZICOM Once Daily (n = 414) SINGLE ATRIPLA Once Daily (n = 419) System Organ Class/ Preferred Term Psychiatric Insomnia <1% <1% 3% 2% Depression <1% <1% 1% 2% Abnormal dreams <1% <1% <1% 2% Nervous System Dizziness <1% <1% <1% 5% Headache <1% <1% 2% 2% Gastrointestinal Nausea 1% 1% <1% 3% Diarrhea <1% <1% <1% 2% Skin and Subcutaneous Tissue Rash a 0 <1% <1% 6% General Disorders Fatigue <1% <1% 2% 2% Ear and Labyrinth Vertigo 0 <1% 0 2% a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting. In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving TIVICAY and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. 7

8 Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen. The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen. Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48. Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials. Less Common Adverse Reactions Observed in Treatment-naïve and Treatmentexperienced Trials The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting. Hepatobiliary Disorders: Hepatitis. Musculoskeletal Disorders: Myositis. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities 8

9 Treatment-naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 3. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-naïve Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysis) SPRING-2 SINGLE TIVICAY Once Raltegravir 400 mg Twice TIVICAY + Laboratory Parameter Daily + Daily + 2 EPZICOM ATRIPLA 2 NRTIs NRTIs Once Daily Once Daily Preferred Term (n = 403) (n = 405) (n = 414) (n = 419) ALT Grade 2 (> x ULN) 4% 4% 2% 5% Grade 3 to 4 (>5.0 x ULN) 2% 2% <1% <1% AST Grade 2 (> x ULN) 5% 3% 3% 3% Grade 3 to 4 (>5.0 x ULN) 3% 2% <1% 3% Total Bilirubin Grade 2 ( x ULN) 3% 2% <1% 0 Grade 3 to 4 (>2.5 x ULN) <1% <1% <1% 0 Creatine kinase Grade 2 ( x ULN) 2% 5% 4% 1% Grade 3 to 4 ( 10.0 x ULN) 7% 4% 5% 7% Hyperglycemia Grade 2 (126-2/dL) 6% 6% 7% 5% Grade 3 (>2/dL) <1% 2% 2% <1% Lipase Grade 2 (> x ULN) 7% 7% 9% 9% Grade 3 to 4 (>3.0 x ULN) 2% 5% 4% 3% Total neutrophils Grade 2 ( x 10 9 ) 4% 3% 3% 5% Grade 3 to 4 (<0.75 x 10 9 ) 2% 2% 2% 3% ULN = Upper limit of normal. 9

10 Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment-naïve Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysis a ) SPRING-2 SINGLE TIVICAY TIVICAY Once Raltegravir + ATRIPLA Laboratory Parameter Daily mg Twice EPZICOM Once 2 NRTIs Daily + 2 NRTIs Once Daily Daily Preferred Term (n = 403) (n = 405) (n = 414) (n = 419) Cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY n = 30 and ATRIPLA n = 27). Seventyseven subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY n = 25 and ATRIPLA: n = 30). Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-experienced, Integrase Strand Transfer Inhibitor-naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials. Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects: The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of 10

11 therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions (5.2)]. Changes in Serum Creatinine Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dl (range: mg per dl to 0.65 mg per dl) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatmentexperienced subjects. 6.2 Clinical Trials Experience in Pediatric Subjects IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatmentexperienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults. 7 DRUG INTERACTIONS 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC 50 = 1.93 µm) and multidrug and toxin extrusion transporter (MATE) 1 (IC 50 = 6.34 µm). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin, Table 5) [see Contraindications (4), Drug Interactions (7.3)]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC 50 = 2.12 µm) and OAT3 (IC 50 = 1.97 µm). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC 50 greater than 50 μm) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the 11

12 results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 5) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]. In vitro, dolutegravir was not a substrate of OATP1B1, or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. 7.3 Established and Other Potentially Significant Drug Interactions Table 5 provides clinical recommendations as a result of drug interactions with TIVICAY. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Dosage and Administration (2), Clinical Pharmacology (12.3).] 12

13 Table 5. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)] Concomitant Drug Class: Drug Name Non-nucleoside reverse transcriptase inhibitor: Etravirine a Non-nucleoside reverse transcriptase inhibitor: Efavirenz a Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents Dolutegravir Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatmentexperienced, INSTI-naïve patients. Non-nucleoside reverse transcriptase inhibitor: Nevirapine Protease Inhibitor: Fosamprenavir/ritonavir a Tipranavir/ritonavir a Dolutegravir Dolutegravir Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations. Adjust dose of TIVICAY to twice daily for treatment-naïve and treatmentexperienced, INSTI-naïve patients. Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Other Agents Carbamazepine a Dolutegravir Adjust dose of TIVICAY to twice daily in treatment-naïve or treatmentexperienced, INSTI-naïve patients. 13

14 Oxcarbazepine Phenytoin Phenobarbital St. John s wort (Hypericum perforatum) Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids a or laxatives Sucralfate Buffered medications Oral calcium or iron supplements, including multivitamins containing calcium or iron a Dolutegravir Dolutegravir Dolutegravir 14 Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations. Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations. Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food. Metformin Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended. Rifampin a Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatmentexperienced, INSTI-naïve patients. Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance

15 substitutions or clinically suspected INSTI resistance. b a See Clinical Pharmacology (12.3) Table 8 or Table 9 for magnitude of interaction. b The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTIassociated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women with HIV exposed to TIVICAY and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 27 times the human dose of twice daily and have revealed no evidence of impaired fertility or harm to the fetus due to TIVICAY. Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 27 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity. Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.4 times the 50-mg twice-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg. 8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human milk. 15

16 Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, instruct mothers not to breastfeed. 8.4 Pediatric Use Safety and efficacy of TIVICAY have not been established in pediatric patients younger than 12 years, weighing less than 40 kg, or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir). The safety, virologic, and immunologic responses in subjects who received TIVICAY were evaluated in 23 treatment-experienced, INSTI-naïve, HIV-1 infected subjects aged 12 to less than 18 years in an open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Pharmacokinetic parameters, evaluated in 9 subjects weighing at least 40 kg receiving daily and 1 subject (weighing 37 kg) receiving 35 mg once daily, were similar to adults receiving once daily. See Dosage and Administration (2.2) for dosing recommendations for pediatric patients aged 12 years and older and weighing at least 40 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.2)]. 8.5 Geriatric Use Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) with 16

17 severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents [see Clinical Pharmacology (12.3)]. Dolutegravir has not been studied in patients on dialysis. 10 OVERDOSAGE There is no known specific treatment for overdose with TIVICAY. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 11 DESCRIPTION TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl- 6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C 20 H 18 F 2 N 3 NaO 5 and the molecular weight is g per mol. It has the following structural formula: F F H N O O ONa N O N H CH 3 O Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Each film-coated tablet of TIVICAY for oral administration contains 52.6 mg of dolutegravir sodium, which is equivalent to dolutegravir free acid, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow, macrogol/peg, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dolutegravir is an HIV-1 antiviral agent [see Microbiology (12.4)] Pharmacodynamics In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy demonstrated rapid and dose-dependent antiviral activity with mean declines from 17

18 baseline to Day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log 10 for dolutegravir 2 mg, 10 mg, and once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50-mg group. Effects on Electrocardiogram In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3 fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose. Effects on Renal Function The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir once daily (n = 12), dolutegravir twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo Pharmacokinetics The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1 infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1 infected subjects. The non-linear exposure of dolutegravir following twice daily compared with once daily in HIV-1 infected subjects (Table 6) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir twice daily in clinical trials. TIVICAY was administered without regard to food in these trials. Table 6. Dolutegravir Steady-state Pharmacokinetic Parameter Estimates in HIV 1 Infected Adults Parameter Once Daily Geometric Mean a (%CV) Twice Daily Geometric Mean b (%CV) AUC (0-24) (mcg.h/ml) 53.6 (27) 75.1 (35) C max (mcg/ml) 3.67 (20) 4.15 (29) C min (mcg/ml) 1.11 (46) 2.12 (47) a Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2. 18

19 b Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3. Absorption Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, C max, and C 24 h ranging from 1.2 to 1.5. Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Effects of Food on Oral Absorption TIVICAY may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir. Low-, moderate-, and high-fat meals increased dolutegravir AUC (0- ) by 33%, 41%, and 66%; increased C max by 46%, 52%, and 67%; and prolonged T max to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. Distribution Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per ml (range: 3.74 ng per ml to 18.3 ng per ml) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established. Metabolism and Elimination Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [ 14 C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose). Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses. Polymorphisms in Drug-metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% 19

20 lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41). Specific Populations Hepatic Impairment: Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child- Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment. HBV/HCV Co-infection: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection. Renal Impairment: Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. In a trial comparing 8 subjects with severe renal impairment (CrCl less than 30 ml per min) with 8 matched healthy controls, AUC, C max, and C 24 of dolutegravir were decreased by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. The cause of this decrease is unknown. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. No dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients requiring dialysis. Gender: Population analyses using pooled pharmacokinetic data from adult trials indicated gender had no clinically relevant effect on the exposure of dolutegravir. Race: Population analyses using pooled pharmacokinetic data from adult trials indicated race had no clinically relevant effect on the pharmacokinetics of dolutegravir. Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. Pediatric Patients: The pharmacokinetics of dolutegravir in HIV-1 infected children (n = 10) aged 12 to less than 18 years were similar to those observed in HIV-1 infected adults who received dolutegravir once daily (Table 7) [see Clinical Studies (14.2)]. 20

21 Table 7. Dolutegravir Steady-state Pharmacokinetic Parameters in Pediatric Subjects Dolutegravir Pharmacokinetic Parameter Estimates Geometric Mean (%CV) Age/Weight Dose of TIVICAY a C max (mcg/ml) (n = 10) AUC (0-24) (mcg.h/ml) (n = 10) C 24 (mcg/ml) (n = 10) 12 to <18 years 3.49 (38) 46 (43) 0.90 (59) and 40 kg a once daily a One subject weighing 37 kg received TIVICAY 35 mg once daily. Drug Interactions Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. As dolutegravir is not expected to affect the pharmacokinetics of other drugs dependent on hepatic metabolism (Table 8) [see Drug Interactions (7.1)], the primary focus of these drug interaction trials was to evaluate the effect of coadministered drug on dolutegravir (Table 9). Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 5 [see Dosage and Administration (2.1), Drug Interactions (7.3)]. 21

22 Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir Coadministered Drug(s) Dose of No Effect = 1.00 and Dose(s) TIVICAY n C max AUC C τ or C 24 Ethinyl estradiol mg twice daily (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Metformin 15 a _ 500 mg twice daily once daily (1.53 to 1.81) (1.65 to 1.93) Metformin 15 a _ 500 mg twice daily twice daily (1.91 to 2.33) (2.25 to 2.66) Methadone 16 to 1 twice daily (0. 94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam 25 mg 10 _ 0.95 _ 3 mg once daily (0.79 to 1.15) Norelgestromin 0.25 mg twice daily (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily once daily (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Tenofovir disoproxil fumarate once daily (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) 300 mg once daily a The number of subjects represents the maximum number of subjects that were evaluated. 22

23 Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs Coadministered Drug(s) Dose of No Effect = 1.00 and Dose(s) TIVICAY n C max AUC C τ or C 24 Atazanavir 400 mg once daily 30 mg once daily (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62 (0.56 to 0.69) Efavirenz 600 mg once daily once daily (0.51 to 0.73) 0.43 (0.35 to 0.54) 0.25 (0.18 to 0.34) Etravirine 200 mg twice daily once daily (0.43 to 0.54) 0.29 (0.26 to 0.34) 0.12 (0.09 to 0.16) Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily once daily (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily Fosamprenavir/ritonavir 700 mg /100 mg twice daily Lopinavir/ritonavir 400/100 mg twice daily Rilpivirine 25 mg once daily Tenofovir 300 mg once daily Tipranavir/ritonavir 500/200 mg twice daily Antacid (Maalox ) simultaneous administration Antacid (Maalox ) 2 h after dolutegravir Boceprevir 800 mg every 8 hours Calcium carbonate 1,200 mg simultaneous administration (fasted) once daily once daily 30 mg once daily once daily once daily once daily single dose single dose once daily single dose (1.02 to 1.13) (0.63 to 0.92) (0.94 to 1.07) (1.06 to 1.21) (0.87 to 1.08) (0.50 to 0.57) (0.23 to 0.33) (0.69 to 0.98) (0.96 to 1.15) (0.50 to 0.81) 1.11 (1.02 to 1.20) 0.65 (0.54 to 0.78) 0.97 (0.91 to 1.04) 1.12 (1.05 to 1.19) 1.01 (0.91 to 1.11) 0.41 (0.38 to 0.44) 0.26 (0.22 to 0.32) 0.74 (0.62 to 0.90) 1.07 (0.95 to 1.20) 0.61 (0.47 to 0.80) 1.28 (1.13 to 1.45) 0.51 (0.41 to 0.63) 0.94 (0.85 to 1.05) 1.22 (1.15 to 1.30) 0.92 (0.82 to 1.04) 0.24 (0.21 to 0.27) 0.26 (0.21 to 0.31) 0.70 (0.58 to 0.85) 1.08 (0.91 to 1.28) 0.61 (0.47 to 0.80) 23